EP1469866B1 - Cycloglycans suitable to inhibit mammalian infection - Google Patents
Cycloglycans suitable to inhibit mammalian infection Download PDFInfo
- Publication number
- EP1469866B1 EP1469866B1 EP03706365A EP03706365A EP1469866B1 EP 1469866 B1 EP1469866 B1 EP 1469866B1 EP 03706365 A EP03706365 A EP 03706365A EP 03706365 A EP03706365 A EP 03706365A EP 1469866 B1 EP1469866 B1 EP 1469866B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- cycloglycans
- ring
- monosaccharides
- use according
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 238000010172 mouse model Methods 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 229940051866 mouthwash Drugs 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 230000014511 neuron projection development Effects 0.000 description 1
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
- 210000001322 periplasm Anatomy 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 235000020610 powder formula Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 235000013580 sausages Nutrition 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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- 239000013589 supplement Substances 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 230000006098 transglycosylation Effects 0.000 description 1
- 238000005918 transglycosylation reaction Methods 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the invention relates to the use in particular of homopolymeric cycloglycans having a ring-shaped basic structure of 2 to 40 monosaccharides in the ring for preventing the invasion and infection of mammalian cells by pathogens and for controlling diseases caused by such pathogens.
- the US-A-5 221 669 describes antiviral agents containing ⁇ -cyclodextrin sulphates alone or together with known antiviral agents. These known agents are said to be effective in inhibiting the infection of the HIV virus.
- cyclodextrin-containing antiviral agents for the control of the HIV virus are also known.
- XP002241408 and JP 03 101754B are concerned with branched cyclodextrins, which are used as preservatives for, inter alia, foods.
- One way to affect such ligand-receptor relationships is by blocking and / or structurally altering the respective receptors on the cell surface or ligands.
- Another possibility is to influence cellular processes at the molecular biological level. This can lead to defense mechanisms being triggered in the mammalian cells, for example, or in the case of the pathogenic microorganisms, the expression of virulence mechanisms (for example shutting down virulence genes in bacteria by blocking central regulators) can be reduced or prevented. In this way, the expression of certain surface structures of pathogenic Listeria, which are responsible for invasion into host cells, can be successfully inhibited by certain carbohydrates such as cellobiose ( Park SF Kroll RH Mol Microbiol 1993 8: 653: 661 ; WO-A 94/02586 ).
- the object of the present invention is to provide a way in which carbohydrates can be used to reduce or prevent the invasion and infection of mammalian cells by pathogens and to effectively combat diseases caused by such pathogens.
- cycloglycans are used to achieve the object of the invention. These cycloglycans are hereinafter referred to as cycloglycans according to the invention.
- cycloglycans according to the invention it is possible to use both individual cycloglycans according to the invention alone or a plurality of cycloglycans according to the invention mixed with one another. Furthermore, it is possible to use a cycloglycan according to the invention or several cycloglycans according to the invention or else a mixture of numerous cycloglycans according to the invention together with other carbohydrates not belonging to the cycloglycans according to the invention in the form of a carbohydrate mixture.
- the cycloglycans according to the invention have 2 to 40 monosaccharides in the ring; they are in themselves monosaccharide units linked to one another, which for the sake of clarity are referred to here only as monosaccharides. These monosaccharides represent a ring polymer.
- the cycloglycans according to the invention can thus be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 35, 36, 37, 38, 39 and 40 have monosaccharides in the ring.
- the cycloglycans of the invention from 6 to 40, more preferably from 6 to 20 and further particularly preferably from 6 to 8 monosaccharides are constructed.
- cycloglycans according to the invention are homopolymeric cycloglycans.
- the ring-shaped basic structure has only monosaccharides of one kind or is composed of the same monosaccharides.
- the ring of the cycloglycans is preferably composed of D-fructose, D-mannose, L-fucose, DN-acetylglucosamine, DN-acetylgalactosamine, D-xylose, sialic acids (eg N-acetylneuraminic acid), L-rhamnose, D-arabinose , D-Allose, D-Talose, L-Idose, D-Ribose, D-Galacturonic Acid, Altrose, D-galactose and Glucoses. These monosaccharides are connected together in a ring and represent the ring of the inventive, in particular homopolymeric cycloglycans.
- the glycosidic linkages in both the ring and the ring-linked glycans can be: ⁇ 1-2, ⁇ 1-3, ⁇ 1-4, ⁇ 1-6, ⁇ 2-3, ⁇ 2-6, ⁇ 2-8, ⁇ 1-2, ⁇ 1-3, ⁇ 1-4, ⁇ 1-6 and ⁇ 2-1.
- the binding of the monosaccharides with one another is preferably ⁇ - or ⁇ -glycosidic.
- Preferred cycloglycans according to the invention are those which have 6, 7 or 8 glucose units in the ring in ⁇ -1-4-glycosidic linkage. These include the ⁇ -, ⁇ - and ⁇ -cyclodextrins mentioned herein and the derivatives thereof.
- the cyclodextrins according to the invention may be underivatized cyclodextrins. It is therefore assumed, without being bound by this statement, that the cyclic structure of the cycloglycans according to the invention is responsible for their effects described in the context of the present documents.
- the cycloglycans according to the invention can also - as stated - be derivatized by one or more functional group (s).
- the substitution may be on the ring itself or on the free Hydroxyl groups of the ring-forming monosaccharides may be present.
- the cycloglycans according to the invention are known compounds or they can be prepared by known processes. Small-ring cycloglycans (for example, with only 2 monosaccharides in the ring) are described in: Armspach D., Gattuso G., King R., Stoddart JF Cyclodextrins in: Bioorganic Chemistry: Carbohydrates. (SM Hecht ed.) Oxford Univ. Press New York 1999 ,
- the cycloglycans according to the invention include the cyclodextrins in which the ring is composed of the monosaccharide or the monosaccharide unit glucose. They occur naturally as ⁇ -, ⁇ - and ⁇ -cyclodextrin. These cyclodextrins are preferably used according to the invention. They are obtained enzymatically from starch by the activity of cyclodextrin glycosyltransferases (CGTases), a microbial enzyme (eg Bacillus macerans). The distinction between the three natural cyclodextrins is based on the number of glucose molecules involved.
- ⁇ -cyclodextrin contains 6, ⁇ -cyclodextrin contains 7, and ⁇ -cyclodextrin contains 8 glycopyranose units, each linked to a ring in ⁇ -1-4 glycosydic bonds.
- Other cyclodextrins with larger molecules, usually containing up to 10 monosaccharide units, are described by way of example MJ Playne & R. Crittenden, Commercial available oligosaccharides, Bulletin of the IDF 313, 1996, 10-22 , Other cycloglycans, favored ⁇ -1-2 linked cycloglycans, are detected in the periplasmic space of various bacteria.
- Ring-shaped molecules consisting of up to 40 monosaccharide units which may be derivatized (in particular on the free hydroxyl groups) are described, for example, in: compare Talaga P., Stahl B., Wieruszeski J.-M., Hillenkamp F., Tsuyumu S., Lippens G., Bohin J.-P., Cell-associated Glucans of Burkholderia solanacearum and Xanthomonas Campestris pv. Citri: a New Family of Periplasmic Glucans; Journal of Bacteriology 1996, 178, 8, 2263-2271 ,
- the cycloglycans according to the invention can be prepared by suitable, known processes chemically, enzymatically or in a coupling of the two technologies. This is done systematically from the monosaccharide components or by modification of suitable oligosaccharide raw materials.
- transferases Leloir, or non-Leloir
- hydrolases reverse hydrolysis or transglycosylation
- the enzymes can be both free and incorporated (such as membrane reactor) or covalently attached to a carrier (for example, beads, Chromatography material or filtration membranes). It is also possible to use pro- or eukaryotic cells for synthesis, provided that these cells have the appropriate enzymes.
- cycloglycans according to the invention are described in the following references or can be prepared by the processes described therein: Armspach D., Gattuso G., Königer R., Stoddart JF Cyclodextrins in: Bioorganic Chemistry: Carbohydrates (SM Hecht ed.) P. 458, Oxford Univ. Press New York 1999 ,
- cycloglycan according to the invention is composed of only two monosaccharides, then it is not substituted; rather, it consists only of the ring of these 2 monosaccharides.
- the cycloglycans of the invention can at least reduce or even prevent the invasion and infection of mammalian cells by pathogens and can be used to combat diseases caused by such pathogens.
- pathogens include invasive Gram-positive and Gram-negative, pathogenic bacteria, for example intracellular bacteria, in particular Listeria, and pathogenic viruses, for example Rotaviruses.
- the cycloglycans according to the invention can prevent the invasion and infection of mammalian cells by Listeria, in particular Listeria monocytogenes.
- the results of the investigations carried out clearly show that neither the process of phagocytosis itself nor the replication of the ingested Listeria is inhibited.
- the cyclodextrins according to the invention proved to be particularly inhibitory.
- the cycloglycans according to the invention have an anti-infective or inhibitory effect in the sense of an infection with Listeria and Salmonella.
- the cycloglycans of the invention can prevent the invasion of listeria in macrophage cell lines. Since the infection of a cell is often preceded by adherence and invasion of the pathogens, there is a transferability to all pathogens whose infection proceeds according to this mechanism of Listeria. These are mainly Salmonella and E. coli.
- the cycloglycans according to the invention can complex other substances and substance classes in order to improve their solubility behavior. According to the invention, however, it has been found that the cycloglycans possess anti-infective properties, which makes it possible to use these compounds for preventing or treating an infection without the need to add further substances. If necessary, of course, further active substances can be used together with the cycloglycans according to the invention.
- the cycloglycans according to the invention can not only be bound as free or unbound cyclooligosaccharides but also to a carrier or immobilized thereon, eg. B adsorbed thereon can be used.
- This carrier can be a peptide / protein (for example BSA), a lipid, (glycolipid, ceramide), a polymer or a biopolymer (for example carbohydrate dendrimer, polysaccharide, polyacrylamide) or any other aglycone.
- the cycloglycans according to the invention can be incorporated in various dietetic and pharmaceutical agents. All of these agents may be in the form suitable for the desired administration, and in particular in liquid or solid form.
- These supplements also include food supplements, beverages, and foods including infant and baby foods.
- baby food or baby food refers in particular to all artificially produced foods.
- artificial here are understood such diets that are made of raw materials of plant and animal origin, but not of human origin.
- These foods can be administered in any manner to a human or animal. This includes administration as a solution for infusion and as a tube feeding into the stomach.
- the cycloglycans according to the invention can also be added to natural milks, for example animal milk.
- the cycloglycans according to the invention can be added, for example, as admixtures or additives to the following products: milk and milk products, infant and child foods, chocolate bars, yoghurt drinks, cheese, sausage and meat products, dietary supplement, tube feed and products for pregnant women and for immunosuppression.
- compositions according to the invention may also be present in the compositions according to the invention, so that the compositions according to the invention have a carbohydrate mixture, the cycloglycans according to the invention forming part of this carbohydrate mixture.
- the cycloglycans of the invention may also be administered in the form of a pharmaceutical agent alone or together with one or more additional active agent (s).
- additional active agent s
- These agents may be formulated, for example, as a tablet / sachet.
- conventional adjuvants, carriers, adjuvants, diluents, moisturizers, Thickeners, flavorings, sweeteners, etc. find application.
- the pharmaceutical agents may be administered to a patient (i.e., human and animal) in any conventional manner.
- a patient i.e., human and animal
- the at least one cycloglycan-containing dietary agent and pharmaceutical agent can be used, inter alia, for the prevention and treatment of infections of the gastrointestinal tract, for example in listeriosis, the blood system, the respiratory tract, the genitourinary tract and the nasopharynx and for the protection of endothelia, epithelia and mucosa become. Thus, they can also be topically applied to the skin or applied to mucous membranes. These mucous membranes include nasal, intestinal, bronchial and vaginal mucous membranes.
- the cycloglycans according to the invention may be added, for example, to a mouthwash.
- Target groups for the cycloglycans according to the invention can be all ages from newborns to seniors. Special areas of application are the protection and treatment of pregnant women, the sick, the weakened and the elderly, in which the avoidance of, for example, listeriosis is of particular importance.
- exemplary dietetics and pharmaceuticals containing at least one cycloglycan of the invention are the following cycloglycans according to the invention: ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, cyclofructins (DP6-8), cyclomannines (DP6-8), cyclogalactins (DP6-8), cycloaltrins (DP6-8), periplasmic Cycloglucans (DP6-25).
- cycloglycans in the examples only with the term cycloglycane designated. This term is representative of any of the above-listed inventive cycloglycan and mixtures thereof.
- sachets For the preparation of sachets, 100 mg of cycloglycan are mixed dry with 990 mg of maltodextrin and then packaged in sachets. These sachets are given three times a day with meals.
- a well-known diet in the form of a perlate with 18.8 g protein, 8.6 g fat, 62.8 g carbohydrates, 3.3 g minerals and vitamins is known in the production per se Cycloglycan is added in an amount such that 50 mg of cycloglycan is contained in 100 g of the finished perlate.
- An effervescent tablet (final weight 4.15 g) ( Neovin® from Milupa) is prepared with the addition of 200 to 500 mg of cycloglycan in a manner known per se. Every day a tablet is dissolved in 150 ml of water and drunk.
- a balanced powdered formula ( Dilsana® from Milupa) with 22.5 g protein, 7.7 g fat, 60.8 g carbohydrates, 5.4 g minerals and vitamins is per se known manner with incorporation of 100 mg produced up to 1000 mg cycloglycan per 100 g powder. Every day up to 3 x 50 g of the food are dissolved in 150 ml of water and administered.
- 100 g of a custom-made instant tea powder are mixed with 2 g of cycloglycan. Each 3.8 g of tea powder are dissolved in 100 ml of hot water and administered three times a day.
- a protein-adapted infant milk formula ( Aptamil® from Milupa) containing 11.8 g protein, 56.9 g carbohydrates, 24.9 g fat, 2.5 g minerals, vitamins and 45 mg taurine is prepared in the usual way in the form of a pearlate, the is mixed with 100 mg to 1000 mg of cycloglycan per 100 g of infant milk formula.
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Abstract
Description
Die Erfindung betrifft die Verwendung von insbesondere homopolymeren Cycloglycanen mit einer ringförmigen Grundstruktur aus 2 bis 40 Monosacchariden im Ring zur Verhinderung der Invasion und Infektion von Säugerzellen durch Pathogene und zur Bekämpfung von durch derartige Pathogene verursachten Erkrankungen.The invention relates to the use in particular of homopolymeric cycloglycans having a ring-shaped basic structure of 2 to 40 monosaccharides in the ring for preventing the invasion and infection of mammalian cells by pathogens and for controlling diseases caused by such pathogens.
Die
Aus der
XP002241408 und
Die Adhäsion sowohl pathogener Organismen als auch zellschädigender Substanzen an die Oberfläche von Säugerzellen ist der erste Schritt und eine unabdingbare Voraussetzung für eine Infektion bzw. Schädigung der Zelle. Die Interaktion zwischen den Pathogenen und den Zellen kommt durch eine Ligand-Rezeptor-Beziehung zustande. Glycostrukturen spielen bei diesen Beziehungen bzw. Wechselwirkungen eine wichtige Rolle.The adhesion of both pathogenic organisms and cell-damaging substances to the surface of mammalian cells is the first step and an indispensable prerequisite for infection or damage to the cell. The interaction between the pathogens and the cells comes about through a ligand-receptor relationship. Glycostructures play an important role in these relationships or interactions.
Eine Möglichkeit, derartige Ligand-Rezeptor-Beziehungen zu beeinflussen, besteht in der Blockierung und/oder der strukturellen Veränderung der jeweiligen Rezeptoren auf der Zelloberfläche oder der Liganden.One way to affect such ligand-receptor relationships is by blocking and / or structurally altering the respective receptors on the cell surface or ligands.
Verschiedene Kohlenhydratmischungen haben sich in spezifischen Testsystemen als sehr wirksam erwiesen, die Adhäsion beispielsweise von Mikroorganismen an die Zelloberfläche zu vermindern oder ganz zu verhindern, man vergleiche:
Eine andere Möglichkeit besteht darin, auf molekularbiologischer Ebene eine Beeinflussung zellulärer Prozesse zu erreichen. Dies kann dazu führen, dass etwa bei den Säugerzellen Abwehrmechanismen ausgelöst werden oder bei den pathogenen Mikroorganismen die Expression von Virulenzmechanismen (z.B. Abschalten von Virulenzgenen bei Bakterien durch Blockierung zentraler Regulatoren) verringert oder verhindert werden. Auf diese Weise kann die Expression bestimmter Oberflächenstrukturen von pathogenen Listerien, die für die Invasion in Wirtszellen verantwortlich sein, durch bestimmte Kohlenhydrate wie Cellobiose erfolgreich gehemmt werden (
Aufgabe der vorliegenden Erfindung ist es, einen Weg aufzuzeigen, wie mit Hilfe von Kohlenhydraten die Invasion und Infektion von Säugerzellen durch Pathogene verringert oder verhindert werden kann und durch derartige Pathogene verursachte Erkrankungen wirksam bekämpft werden können.The object of the present invention is to provide a way in which carbohydrates can be used to reduce or prevent the invasion and infection of mammalian cells by pathogens and to effectively combat diseases caused by such pathogens.
Gelöst wird diese Aufgabe durch die Lehre der Ansprüche.This problem is solved by the teaching of the claims.
Erfindungsgemäß werden spezielle Cycloglycane zur Lösung der erfindungsgemäßen Aufgabe zur Anwendung gebracht. Diese Cycloglycane werden nachstehend als erfindungsgemäße Cycloglycane bezeichnet.According to the invention, special cycloglycans are used to achieve the object of the invention. These cycloglycans are hereinafter referred to as cycloglycans according to the invention.
Erfindungsgemäß können sowohl einzelne erfindungsgemäße Cycloglycane alleine oder mehrere erfindungsgemäße Cycloglycanen in Mischung miteinander eingesetzt werden. Ferner ist es möglich, ein erfindungsgemäßes Cycloglycan oder mehrere erfindungsgemäße Cycloglycane oder auch eine Mischung von zahlreichen erfindungsgemäßen Cycloglycanen zusammen mit anderen, nicht zu den erfindungsgemäßen Cycloglycanen zählenden Kohlenhydraten in Form einer Kohlenhydratmischung einzusetzen.According to the invention, it is possible to use both individual cycloglycans according to the invention alone or a plurality of cycloglycans according to the invention mixed with one another. Furthermore, it is possible to use a cycloglycan according to the invention or several cycloglycans according to the invention or else a mixture of numerous cycloglycans according to the invention together with other carbohydrates not belonging to the cycloglycans according to the invention in the form of a carbohydrate mixture.
Die erfindungsgemäßen Cycloglycane weisen im Ring 2 bis 40 Monosaccharide auf; an sich handelt es sich dabei um mit einander verbundene Monosaccharid-Einheiten, die der besseren Darstellung halber hier nur als Monosaccharide bezeichnet werden. Diese Monosaccharide stellen ein Ringpolymer dar. Die erfindungsgemäßen Cycloglycane können somit 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 35, 36, 37, 38, 39 und 40 Monosaccharide im Ring besitzen.The cycloglycans according to the invention have 2 to 40 monosaccharides in the ring; they are in themselves monosaccharide units linked to one another, which for the sake of clarity are referred to here only as monosaccharides. These monosaccharides represent a ring polymer. The cycloglycans according to the invention can thus be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 35, 36, 37, 38, 39 and 40 have monosaccharides in the ring.
Vorzugsweise sind die erfindungsgemäßen Cycloglycane aus 6 bis 40, insbesondere bevorzugt aus 6 bis 20 und weiterhin insbesondere bevorzugt aus 6 bis 8 Monosacchariden aufgebaut.Preferably, the cycloglycans of the invention from 6 to 40, more preferably from 6 to 20 and further particularly preferably from 6 to 8 monosaccharides are constructed.
Weiterhin bevorzugt handelt es sich bei den erfindungsgemäßen Cycloglycanen um homopolymere Cycloglycane. Mit anderen Worten, die ringförmige Grundstruktur weist nur Monosaccharide einer Art auf bzw. ist aus denselben Monosacchariden aufgebaut.With further preference the cycloglycans according to the invention are homopolymeric cycloglycans. In other words, the ring-shaped basic structure has only monosaccharides of one kind or is composed of the same monosaccharides.
Der Ring der Cycloglycane ist vorzugsweise aufgebaut aus D-Fructose, D-Mannose, L-Fucose, D-N-Acetylglucosamin, D-N-Acetylgalactosamin, D-Xylose, Sialinsäuren (z. B. N-Acetylneuraminsäure), L-Rhamnose, D-Arabinose, D-Allose, D-Talose, L-Idose, D-Ribose, D-Galacturonsäure, Altrose, D-Galactose und Glucosen. Diese Monosaccharide sind ringförmig miteinander verbunden und stellen den Ring der erfindungsgemäßen, insbesondere homopolymeren Cycloglycane dar.The ring of the cycloglycans is preferably composed of D-fructose, D-mannose, L-fucose, DN-acetylglucosamine, DN-acetylgalactosamine, D-xylose, sialic acids (eg N-acetylneuraminic acid), L-rhamnose, D-arabinose , D-Allose, D-Talose, L-Idose, D-Ribose, D-Galacturonic Acid, Altrose, D-galactose and Glucoses. These monosaccharides are connected together in a ring and represent the ring of the inventive, in particular homopolymeric cycloglycans.
Bei den Cycloglycanen können die glycosidischen Verknüpfungen sowohl im Ring als auch bei den mit dem Ring verknüpften, nachstehend näher beschriebenen Glycanen folgende sein: α1-2, α1-3, α1-4, α1-6, α2-3, α2-6, α2-8, β1-2, β1-3, β1-4, β1-6 und β2-1.In the case of the cycloglycans, the glycosidic linkages in both the ring and the ring-linked glycans, which are described in more detail below, can be: α1-2, α1-3, α1-4, α1-6, α2-3, α2-6, α2-8, β1-2, β1-3, β1-4, β1-6 and β2-1.
Die Bindung der Monosaccharide untereinander ist vorzugsweise α- oder β-glycosidisch. Bevorzugte erfindungsgemäße Cycloglycane sind solche, die 6, 7 oder 8 Glucoseeinheiten im Ring in α-1-4-glycosidischer Verknüpfung aufweisen. Dazu zählen die hier genannten α-, β- und γ-Cyclodextrine und die Derivate davon.The binding of the monosaccharides with one another is preferably α- or β-glycosidic. Preferred cycloglycans according to the invention are those which have 6, 7 or 8 glucose units in the ring in α-1-4-glycosidic linkage. These include the α-, β- and γ-cyclodextrins mentioned herein and the derivatives thereof.
Bei den erfindungsgemäßen Cyclodextrinen kann es sich um underivatisierte Cyclodextrine handeln. Es wird daher davon ausgegangen, ohne an dieser Erklärung gebunden zu sein, dass der ringförmige Aufbau der erfindungsgemäßen Cycloglycane für deren im Rahmen der hier vorliegenden Unterlagen beschriebenen Wirkungen verantwortlich ist.The cyclodextrins according to the invention may be underivatized cyclodextrins. It is therefore assumed, without being bound by this statement, that the cyclic structure of the cycloglycans according to the invention is responsible for their effects described in the context of the present documents.
Die erfindungsgemäßen Cycloglycane können auch - wie gesagt - derivatisiert sein, und zwar durch eine oder mehrere funktionelle Gruppe(n). Die Substitution kann am Ring selbst oder an den freien Hydroxylgruppen der diesen Ring bildenden Monosaccharide vorhanden sein.The cycloglycans according to the invention can also - as stated - be derivatized by one or more functional group (s). The substitution may be on the ring itself or on the free Hydroxyl groups of the ring-forming monosaccharides may be present.
Bevorzugte derivatisierte Cycloglycane sind solche, bei denen eines oder alle der folgenden Merkmale erfüllt sind:
- i) eine oder mehrere der OH-Gruppen eines oder mehrerer der den Ring bildenden Monosaccharide ist bzw. sind durch eine NH2-, SH-, Phosphat-Sulfat-, Nitrat-, Alkyl-, Hydroxyalkyl- oder Carboxyalkyl-Gruppe ersetzt. Bei den Alkyl-, Carboxyalkyl- und Hydroxyalkyl-Gruppen weist der Alkylrest vorzugsweise 1 bis 6 Kohlenstoffatome auf. Die den Ring bildenden Monosaccharide können somit beispielsweise durch eine oder mehrere Methyl-, Ethyl-, Hydroxyethyl-, Carboxymethyl- und Hydroxypropyl-Gruppen, um nur einige zu nennen, derivatisiert sein.
- ii) eine oder mehrere der OH-Gruppen sowie der eventuell vorhandenen NH2- und SH-Gruppen der den Ring bildenden Monosaccharide sind in Form von Ethern, Estern, Amiden und Iminen derivatisiert. Bei diesen Derivaten kann es sich beispielsweise um Succinyl-, Acyl- (insbesondere mit 1 bis 25 C-Atomen, weiterhin insbesondere mit 1, 2, 3, 4, 5, oder 6 C-Atomen, z. B. Acetyl-) Methylmalonsäureester-, Phosphoglyceryl- und Phosphocholinyl-Derivate handeln. Zu den Acylderivaten zählen ferner insbesondere solche mit ernährungsphysiologisch wertvollen gesättigten und ungesättigten Fettsäuren mit 12 bis 22 C-Atomen
- i) one or more of the OH groups of one or more of the ring-forming monosaccharides is or have been replaced by an NH 2 , SH, phosphate sulfate, nitrate, alkyl, hydroxyalkyl or carboxyalkyl group. In the alkyl, carboxyalkyl and hydroxyalkyl groups, the alkyl group preferably has 1 to 6 carbon atoms. Thus, the monosaccharides forming the ring may be derivatized by, for example, one or more methyl, ethyl, hydroxyethyl, carboxymethyl and hydroxypropyl groups, to name but a few.
- ii) one or more of the OH groups and any NH 2 and SH groups of the ring-forming monosaccharides are derivatized in the form of ethers, esters, amides and imines. These derivatives may, for example, be succinyl, acyl (in particular having 1 to 25 carbon atoms, more particularly having 1, 2, 3, 4, 5 or 6 carbon atoms, for example acetyl) methylmalonic acid esters , Phosphoglyceryl and phosphocholinyl derivatives act. The acyl derivatives further include in particular those with nutritionally valuable saturated and unsaturated fatty acids having 12 to 22 carbon atoms
Weiterhin bevorzugte erfindungsgemäße Cycloglycane sind folgende:
- Hydroxypropyl-Cyclodextrine, Cyclofructine, Cyclomannine, Cyclogalactine und Cycloaltrine.
- Hydroxypropyl cyclodextrins, cyclofructins, cyclomannins, cyclogalactins and cycloaltrins.
Bei den erfindungsgemäßen Cycloglycanen handelt es sich um bekannte Verbindungen oder sie können nach bekannten Verfahren hergestellt werden. Cycloglycane aus kleinen Ringen (beispielsweise mit nur 2 Monosacchariden im Ring) sind beschrieben in:
Zu den erfindungsgemäßen Cycloglycanen zählen die Cyclodextrine, bei denen der Ring aus dem Monosaccharid bzw. der Monosaccharideinheit Glucose aufgebaut ist. Sie kommen in natürlicher Weise als α-, β- und γ-Cyclodextrin vor. Diese Cyclodextrine werden bevorzugt erfindungsgemäß eingesetzt. Sie werden enzymatisch aus Stärke durch die Aktivität von Cyclodextrin Glycosyltransferasen (CGTasen), einem mikrobiellen Enzym (z. B. Bacillus macerans), gewonnen. Die Unterscheidung in die drei natürlichen Cyclodextrine basiert auf der Anzahl der beteiligten Glucose-Moleküle. α-Cyclodextrin beinhaltet 6, β-Cyclodextrin beinhaltet 7 und γ-Cyclodextrin beinhaltet 8 Glycopyranoseeinheiten, die jeweils in α-1-4-glycosydischen Bindungen zu einem Ring verknüpft sind. Weitere Cyclodextrine mit größeren Molekülen mit üblicherweise bis zu 10 Monosaccharideinheiten sind beilspielsweise beschrieben in
Die erfindungsgemäßen Cycloglycane können nach geeigneten, bekannten Verfahren chemisch, enzymatisch oder in einer Kopplung beider Technologien hergestellt. Diese erfolgt systematisch aus den Monosaccharidbestandteilen oder durch Modifizierung geeigneter Oligosaccharid-Rohstoffe. Bei den enzymatischen Synthesen werden sowohl Transferasen (Leloir, bzw. nicht-Leloir) als auch Hydrolasen (reverse Hydrolyse bzw. Transglycosylierung) eingesetzt. Die Enzyme können dabei sowohl frei als auch eingebunden (etwa Membranreaktor) oder kovalent an einen Träger (beispielsweise beads, Chromatographiematerial oder Filtrationsmembranen) gebunden sein. Es ist auch möglich, pro- oder eukaryontische Zellen zur Synthese einzusetzen, sofern diese Zellen die geeigneten Enzyme aufweisen. Bezüglich weiterer Einzelheiten der Herstellung der erfindungsgemäßen Cycloglycane wird beispielsweise verwiesen auf Carbohydrates in
Weitere erfindungsgemäße Cycloglycane sind an folgenden Literaturstellen beschrieben oder können nach den dort beschriebenen Verfahren hergestellt werden:
Ergänzend wird auf folgendes hingewiesen. Ist das erfindungsgemäße Cycloglycan nur aus 2 Monosacchariden aufgebaut, dann ist es nicht substituiert; vielmehr besteht es nur aus dem Ring aus diesen 2 Monosacchariden.In addition, the following is pointed out. If the cycloglycan according to the invention is composed of only two monosaccharides, then it is not substituted; rather, it consists only of the ring of these 2 monosaccharides.
Es wurde nun überraschend gefunden, dass die erfindungsgemäßen Cycloglycane die Invasion und Infektion von Säugerzellen durch Pathogene zumindest verringern oder sogar verhindern und zur Bekämpfung von durch derartige Pathogene verursachte Erkrankungen eingesetzt werden können. Zu diesen Pathogenen zählen invasive gram-positive und gram-negative, pathogene Bakterien, beispielsweise intrazelluläre Bakterien, insbesondere Listerien, und pathogene Viren, beispielsweise Rotaviren.It has now surprisingly been found that the cycloglycans of the invention can at least reduce or even prevent the invasion and infection of mammalian cells by pathogens and can be used to combat diseases caused by such pathogens. These pathogens include invasive Gram-positive and Gram-negative, pathogenic bacteria, for example intracellular bacteria, in particular Listeria, and pathogenic viruses, for example Rotaviruses.
Es wurde beispielsweise gefunden, dass die erfindungsgemäßen Cycloglycane die Invasion und Infektion von Säugerzellen durch Listerien, insbesondere Listeria monocytogenes verhindern können. Die Ergebnisse der durchgeführten Untersuchungen zeigen deutlich, dass weder der Vorgang der Phagozytose an sich, noch die Replikation der aufgenommenen Listerien gehemmt wird. Als besonders stark inhibitorisch erwies sich unter anderem die erfindungsgemäßen Cyclodextrine.It has been found, for example, that the cycloglycans according to the invention can prevent the invasion and infection of mammalian cells by Listeria, in particular Listeria monocytogenes. The results of the investigations carried out clearly show that neither the process of phagocytosis itself nor the replication of the ingested Listeria is inhibited. Among other things, the cyclodextrins according to the invention proved to be particularly inhibitory.
Insgesamt konnte festgestellt werden, dass die erfindungsgemäßen Cycloglycane eine antiinfektive bzw. inhibitorische Wirkung im Sinne einer Infektion mit Listerien und Salmonellen besitzen. Die erfindungsgemäßen Cycloglycane können die Invasion von Listerien in Makrophagen-Zelllinien verhindern. Da der Infektion einer Zelle häufig eine Adhärenz und eine Invasion der Pathogene vorausgeht, ist eine Übertragbarkeit auf alle Pathogene gegeben, deren Infektion nach diesem Mechanismus der Listerien verläuft. Es sind dies vor allem Salmonellen und E. coli.Overall, it was found that the cycloglycans according to the invention have an anti-infective or inhibitory effect in the sense of an infection with Listeria and Salmonella. The cycloglycans of the invention can prevent the invasion of listeria in macrophage cell lines. Since the infection of a cell is often preceded by adherence and invasion of the pathogens, there is a transferability to all pathogens whose infection proceeds according to this mechanism of Listeria. These are mainly Salmonella and E. coli.
Bisher war von den erfindungsgemäßen Cycloglycanen nur bekannt, dass sie andere Substanzen und Substanzklassen komplexieren können, um deren Löslichkeitsverhalten zu verbessern. Erfindungsgemäß konnte jedoch festgestellt werden, dass die Cycloglycane anti-infektive Eigenschaften besitzen, wodurch diese Verbindungen zur Verhinderung oder Therapie einer Infektion eingesetzt werden können, ohne dass ein Zusatz weiterer Substanzen erforderlich ist. Erforderlichenfalls können natürlich auch weitere Wirksubstanzen zusammen mit den erfindungsgemäßen Cycloglycanen zur Anwendung gelangen.So far, it has only been known of the cycloglycans according to the invention that they can complex other substances and substance classes in order to improve their solubility behavior. According to the invention, however, it has been found that the cycloglycans possess anti-infective properties, which makes it possible to use these compounds for preventing or treating an infection without the need to add further substances. If necessary, of course, further active substances can be used together with the cycloglycans according to the invention.
Die erfindungsgemäßen Cycloglycane können nicht nur als freie bzw. ungebundene Cyclooligosaccharide sondern auch an einen Träger gebunden oder daran immobilisiert, z. B daran adsorbiert, eingesetzt werden. Bei diesem Träger kann es sich um ein Peptid/Protein (beispielsweise BSA), ein Lipid, (Glycolipid, Ceramid), ein Polymer oder ein Biopolymer (beispielsweise Kohlenhydrat-Dendrimer, Polysaccharid, Polyacrylamid) oder jedes andere Aglykon handeln.The cycloglycans according to the invention can not only be bound as free or unbound cyclooligosaccharides but also to a carrier or immobilized thereon, eg. B adsorbed thereon can be used. This carrier can be a peptide / protein (for example BSA), a lipid, (glycolipid, ceramide), a polymer or a biopolymer (for example carbohydrate dendrimer, polysaccharide, polyacrylamide) or any other aglycone.
Die erfindungsgemäßen Cycloglycane, seien es nun ungebundene bzw. freie Cycloglycane oder an einen Träger gebundene Cycloglycane, können verschiedenen diätetischen Mitteln und pharmazeutischen Mitteln einverleibt sein. Alle diese Mittel können in der für die gewünschte Verabreichung geeigneten Form und insbesondere in flüssiger oder fester Form vorliegen. Zu diesen Mitteln zählen auch Nahrungsergänzungsmittel, Getränke sowie Nahrungen einschließlich Säuglings- und Babynahrungen. Der Begriff Babynahrung bzw. Säuglingsnahrung bezeichnet insbesondere alle künstlich hergestellten Nahrungen. Als "künstlich" werden hier solche Nahrungen verstanden, die aus Rohstoffen pflanzlichen und tierischen Ursprungs, jedoch nicht humanen Ursprungs, hergestellt werden. Diese Nahrungen können auf beliebige Weise an einen Menschen oder ein Tier verabreicht werden. Dazu zählt auch die Verabreichung als Infusionslösung und als Sondennahrung in den Magen. Die erfindungsgemäßen Cycloglycane können jedoch auch natürlichen Milchen, beispielsweise Tiermilchen hinzugefügt werden.The cycloglycans according to the invention, whether they are unbound or free cycloglycans or supported cycloglycans, can be incorporated in various dietetic and pharmaceutical agents. All of these agents may be in the form suitable for the desired administration, and in particular in liquid or solid form. These supplements also include food supplements, beverages, and foods including infant and baby foods. The term baby food or baby food refers in particular to all artificially produced foods. As "artificial" here are understood such diets that are made of raw materials of plant and animal origin, but not of human origin. These foods can be administered in any manner to a human or animal. This includes administration as a solution for infusion and as a tube feeding into the stomach. However, the cycloglycans according to the invention can also be added to natural milks, for example animal milk.
Die erfindungsgemäßen Cycloglycane können beispielsweise als Beimengungen oder Additive folgenden Produkten zugegeben werden, wobei diese Aufzählung nicht abschließend ist: Milch und Milchprodukte, Säuglings- und Kindernahrungen, Schokoriegel, Joghurtgetränke, Käse-, Wurst- und Fleischwaren, Aufbaunahrung, Sondennahrung und Produkten für Schwangere und zur Immunsuppression.The cycloglycans according to the invention can be added, for example, as admixtures or additives to the following products: milk and milk products, infant and child foods, chocolate bars, yoghurt drinks, cheese, sausage and meat products, dietary supplement, tube feed and products for pregnant women and for immunosuppression.
Neben den erfindungsgemäßen Cycloglycanen können in den erfindungsgemäßen Mittel auch weitere Kohlenhydrate vorhanden sein, so dass die erfindungsgemäßen Mittel ein Kohlenhydratmischung aufweisen, wobei die erfindungsgemäßen Cycloglycane ein Teil dieser Kohlenhydratmischung darstellen.In addition to the cycloglycans according to the invention, other carbohydrates may also be present in the compositions according to the invention, so that the compositions according to the invention have a carbohydrate mixture, the cycloglycans according to the invention forming part of this carbohydrate mixture.
Die erfindungsgemäßen Cycloglycane können auch in Form eines pharmazeutischen Mittels alleine oder zusammen mit einem oder mehreren zusätzlichen Wirkstoff(en) verabreicht werden. Diese Mittel können beispielsweise als Tablette/Sachet formuliert sein. Für die Formulierung derartiger Pharmazeutika können übliche Adjuvantien, Träger, Hilfsmittel Verdünnungsmittel, feucht-haltende Mitteln, Verdickungsmittel, Geschmacksstoffe, Süßungsmittel usw. Anwendung finden.The cycloglycans of the invention may also be administered in the form of a pharmaceutical agent alone or together with one or more additional active agent (s). These agents may be formulated, for example, as a tablet / sachet. For the formulation of such pharmaceuticals, conventional adjuvants, carriers, adjuvants, diluents, moisturizers, Thickeners, flavorings, sweeteners, etc. find application.
Die pharmazeutischen Mittel können auf jede übliche Weise an einen Patienten (d.h. Mensch und Tier) verabreicht werden. Zweckmäßigerweise handelt es sich jedoch um Mittel, die zur oralen, lingualen, nasalen, intestinalen, bronchialen, vaginalen, topischen (Haut und Schleimhaut) und per os Verabreichung geeignet und entsprechend der Verabreichungsart formuliert sind.The pharmaceutical agents may be administered to a patient (i.e., human and animal) in any conventional manner. Conveniently, however, are agents which are suitable for oral, lingual, nasal, intestinal, bronchial, vaginal, topical (skin and mucous membrane) and per os administration and formulated according to the mode of administration.
Die mindestens ein erfindungsgemäßes Cycloglycan enthaltenden diätetischen Mittel und pharmazeutischen Mittel können unter anderem zur Prävention und Behandlung von Infektionen des Gastrointestinaltraktes, beispielsweise bei Listeriosen, des Blutsystems, der Atemwege, des Urogenitaltraktes sowie des Nasen-Rachenraumes und zum Schutz von Endothelien, Epithelien und Mukosa eingesetzt werden. Sie können somit auch topisch auf die Haut aufgetragen oder auch auf Schleimhäuten Anwendung finden. Zu diesen Schleimhäuten zählen nasale, intestinale, bronchiale und vaginale Schleimhäute. So können die erfindungsgemäßen Cycloglycane beispielsweise einem Mundspülmittel beigefügt sein. Als Zielgruppen für die erfindungsgemäßen Cycloglycane können alle Altersstufen von Neugeborenen bis zu Senioren genannt werden. Besondere Einsatzgebiete sind der Schutz und die Behandlung von Schwangeren, Kranken, geschwächten und älteren Menschen, bei denen die Vermeidung beispielsweise einer Listeriose von besonderer Bedeutung ist.The at least one cycloglycan-containing dietary agent and pharmaceutical agent can be used, inter alia, for the prevention and treatment of infections of the gastrointestinal tract, for example in listeriosis, the blood system, the respiratory tract, the genitourinary tract and the nasopharynx and for the protection of endothelia, epithelia and mucosa become. Thus, they can also be topically applied to the skin or applied to mucous membranes. These mucous membranes include nasal, intestinal, bronchial and vaginal mucous membranes. Thus, the cycloglycans according to the invention may be added, for example, to a mouthwash. Target groups for the cycloglycans according to the invention can be all ages from newborns to seniors. Special areas of application are the protection and treatment of pregnant women, the sick, the weakened and the elderly, in which the avoidance of, for example, listeriosis is of particular importance.
Nachstehend sind beispielhafte Diätetika und Pharmazeutika aufgeführt, welche mindestens ein erfindungsgemäßes Cycloglycan enthalten. Es handelt sich dabei um folgende erfindungsgemäße Cycloglycane: α-Cyclodextrin, β-Cyclodextrin, γ-Cyclodextrin, Cyclofructine (DP6-8), Cyclomannine (DP6-8), Cyclogalactine (DP6-8), Cycloaltrine (DP6-8), periplasmatische Cycloglucane (DP6-25). Der Einfachheit halber werden diese Cycloglycane in den Beispielen nur mit dem Begriff Cycloglycan bezeichnet. Dieser Begriff steht stellvertretend für jedes oben aufgeführte, erfindungsgemäße Cycloglycan und deren Mischungen.Listed below are exemplary dietetics and pharmaceuticals containing at least one cycloglycan of the invention. These are the following cycloglycans according to the invention: α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, cyclofructins (DP6-8), cyclomannines (DP6-8), cyclogalactins (DP6-8), cycloaltrins (DP6-8), periplasmic Cycloglucans (DP6-25). For the sake of simplicity, these cycloglycans in the examples only with the term cycloglycane designated. This term is representative of any of the above-listed inventive cycloglycan and mixtures thereof.
Zur Herstellung von Sachets werden jeweils 100 mg Cycloglycan mit 990 mg Maltodextrin trocken gemischt und dann in Sachets verpackt. Diese Sachets werden dreimal täglich zu den Mahlzeiten verabreicht.For the preparation of sachets, 100 mg of cycloglycan are mixed dry with 990 mg of maltodextrin and then packaged in sachets. These sachets are given three times a day with meals.
Eine bekannte Heilnahrung (d.h. Milupa® HN 25, bilanzierte Diät) in Form eines Perlates mit 18,8 g Eiweiß, 8,6 g Fett, 62,8 g Kohlenhydrate, 3,3 g Mineralstoffen und Vitaminen wird bei der per se bekannten Herstellung mit Cycloglycan in einer solchen Menge versetzt, dass 50 mg Cycloglycan in 100 g des fertigen Perlats enthalten sind.A well-known diet (ie Milupa® HN 25, balanced diet) in the form of a perlate with 18.8 g protein, 8.6 g fat, 62.8 g carbohydrates, 3.3 g minerals and vitamins is known in the production per se Cycloglycan is added in an amount such that 50 mg of cycloglycan is contained in 100 g of the finished perlate.
Für die Herstellung einer flüssigen Heilnahrung werden 100 ml der bekannten Heilnahrung Milupa HN 25 flüssig (2,3 g Eiweiß, 1,6 g Fett, 8,5 g Kohlenhydrate, 37 g Mineralstoffe, Vitamine) mit 7 mg Cycloglycan versetzt.For the production of liquid medicinal food, 100 ml of the known medicinal product Milupa HN 25 liquid (2.3 g protein, 1.6 g fat, 8.5 g carbohydrates, 37 g minerals, vitamins) are mixed with 7 mg cycloglycan.
Eine Brausetablette (Endgewicht 4,15 g) (Neovin® von Milupa) wird unter Beimengung von 200 bis 500 mg Cycloglycan auf per se bekannte Weise hergestellt. Täglich wird eine Tablette in 150 ml Wasser gelöst und getrunken.An effervescent tablet ( final weight 4.15 g) ( Neovin® from Milupa) is prepared with the addition of 200 to 500 mg of cycloglycan in a manner known per se. Every day a tablet is dissolved in 150 ml of water and drunk.
Eine bilanzierte pulverförmige Aufbaunahrung (Dilsana® von Milupa) mit 22,5 g Eiweiß, 7,7 g Fett, 60,8 g Kohlenhydrate, 5,4 g Mineralstoffen und Vitaminen wird auf per se bekannte Weise unter Einarbeitung von 100 mg bis 1000 mg Cycloglycan pro 100 g Pulver hergestellt. Täglich werden bis zu 3 x 50 g der Nahrung in 150 ml Wasser gelöst und verabreicht.A balanced powdered formula ( Dilsana® from Milupa) with 22.5 g protein, 7.7 g fat, 60.8 g carbohydrates, 5.4 g minerals and vitamins is per se known manner with incorporation of 100 mg produced up to 1000 mg cycloglycan per 100 g powder. Every day up to 3 x 50 g of the food are dissolved in 150 ml of water and administered.
100 g eines auf übliche Weise hergestellten Instant-Tee-Pulvers werden mit 2 g Cycloglycan vermengt. Je 3,8 g Teepulver werden in 100 ml heißem Wasser gelöst und dreimal täglich verabreicht.100 g of a custom-made instant tea powder are mixed with 2 g of cycloglycan. Each 3.8 g of tea powder are dissolved in 100 ml of hot water and administered three times a day.
Eine im Eiweiß adaptierte Säuglingsmilchnahrung (Aptamil® von Milupa) mit 11,8 g Eiweiß, 56,9 g Kohlenhydrate24,9 g Fett, 2,5 g Mineralstoffen, Vitaminen und 45 mg Taurin wird auf übliche Weise in Form eines Perlates hergestellt, das mit 100 mg bis 1000 mg Cycloglycan pro 100 g Säuglingsmilchnahrung vermengt wird.A protein-adapted infant milk formula ( Aptamil® from Milupa) containing 11.8 g protein, 56.9 g carbohydrates, 24.9 g fat, 2.5 g minerals, vitamins and 45 mg taurine is prepared in the usual way in the form of a pearlate, the is mixed with 100 mg to 1000 mg of cycloglycan per 100 g of infant milk formula.
Claims (16)
- Use of cycloglycans having a ring-shaped base structure of 2 to 40 monosaccharides in the ring, which is unsubstituted or may be derivatized at the monosaccharides forming said ring, by one or more functional group(s), wherein said cycloglycans may also be bound to an inert carrier or may be immobilized thereon,
for preparing an dietetic composition or a pharmaceutical composition for reducing or preventing the invasion and infection of mammalian cells by invasive gram-positive and gram-negative pathogenic bacteria, and for combating diseases caused by such bacteria. - Use according to claim 1,
characterized in that
the cycloglycans are homopolymeric cycloglycans and/or the ring of the cycloglycans is made up of 6 to 40, and in particular 6 to 20 monosaccharides. - Use according to claim 1 or 2,
characterized in that
the ring of the cycloglycans is made up of D-fructose, D-mannose, L-fucose, D-N-acetyl glucosamine, D-N-acetyl galactosamine, D-xylose, sialic acids, L-rhamnose, D-arabinose, D-allose, D-talose, L-idose, D-ribose, D-galacturonic acid, altrose, D-galactose and glucoses. - Use according to any one of the preceding claims,
characterized in that
one or both of the following criteria are met:i) one or more of the OH groups of one or more of the monosaccharides forming the ring is or are substituted by an NH2 group, SH group, phosphate group, sulfate group, nitrate group, alkyl group, hydroxyalkyl group or carboxyalkyl group.ii) one or more of the OH groups as well as of the - if present - NH2 and SH groups of the monosaccharides forming the ring are derivatized in the form of ethers, esters, amides and imines. - Use according to any one of the preceding claims,
characterized in that
the linkage of the monosaccharides in the ring is α-glycosidic or β-glycosidic, with the β-glycosidically linked monosaccharides in particular being periplasmic glycans. - Use according to any one of the preceding claims,
characterized in that
the cycloglycans have 6, 7 or 8 monosaccharides and in particular glucose units in the ring. - Use according to claim 1,
characterized in that
the cycloglycans are the following:α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin; cyclofructines, cyclomannines, cyclogalactines and cycloaltrines, which may be derivatized in the manner described in claim 4. - Use according to claim 7,
characterized in that
the derivatized cycloglycans are hydroxypropyl cyclodextrins. - Use according to any one of the preceding claims,
characterized in that
the carrier is a peptide, a protein, a lipid, a lipoid, a polymer or a biopolymer. - Use according to claim 10,
characterized in that
the composition serves for an oral, lingual, nasal, bronchial, vaginal, topical (skin and mucosa) and per os administration, for an administration by means of a probe into the stomach of a human or an animal, or for an administration as an infusion. - Use according to any one of the preceding claims,
characterized in that
the cycloglycans are administered once daily in an amount of at least 1 mg per kg of body weight to a human or an animal. - Use according to any one of the preceding claims,
for the prevention and treatment of infections of the gastrointestinal tract, blood system, respiratory passages, urogenital tract, as well as the nasopharynx, in particular in case of listerioses. - Use according to any one of the preceding claims,
characterized in that
the bacteria are listeria. - Composition according to any one of the preceding claims,
characterized in that
it may contain a further carbohydrate or more further carbohydrates, which are not a cycloglycan as described in claim 1, a further active agent or several further active agents and/or a further ingredient, which is known and suited for the corresponding composition, or more of such ingredients, wherein in the case of a pharmaceutical composition a usual auxiliary agent or several usual auxiliary agents, including diluents, moisturizing agents, thickening agents, flavoring agents, sweetening agents and carriers, may be present. - Cycloglycans having a ring-shaped base structure of 2 to 40 monosaccharides in the ring, which is unsubstituted or may be derivatized at the monosaccharides forming said ring by one or more functional group(s), wherein said cycloglycans may also be bound to an inert carrier or immobilized thereon,
for the use in the reduction or prevention of the invasion and infection of mammalian cells by invasive gram-positive and gram-negative pathogenic bacteria, and for combating diseases caused by such bacteria. - Cycloglycans according to claim 15,
characterized in that
they are those as described in at least one of the claims 2 to 9.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10203999A DE10203999A1 (en) | 2002-02-01 | 2002-02-01 | Cycloglycane |
| DE10203999 | 2002-02-01 | ||
| PCT/EP2003/000505 WO2003063882A1 (en) | 2002-02-01 | 2003-01-20 | Cycloglycans suitable to inhibit mammalian infection |
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| Publication Number | Publication Date |
|---|---|
| EP1469866A1 EP1469866A1 (en) | 2004-10-27 |
| EP1469866B1 true EP1469866B1 (en) | 2009-05-13 |
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| US (1) | US20050222080A1 (en) |
| EP (1) | EP1469866B1 (en) |
| CN (1) | CN1627949A (en) |
| AT (1) | ATE431153T1 (en) |
| DE (2) | DE10203999A1 (en) |
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Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US4020160A (en) * | 1975-08-15 | 1977-04-26 | American Cyanamid Company | Cyclodextrin sulfate salts as complement inhibitors |
| JPS5830032B2 (en) * | 1981-02-18 | 1983-06-27 | 呉羽化学工業株式会社 | Bifidus bacteria growth agent |
| US4616008A (en) * | 1984-05-02 | 1986-10-07 | Takeda Chemical Industries, Ltd. | Antibacterial solid composition for oral administration |
| NZ225045A (en) * | 1987-07-01 | 1990-06-26 | Janssen Pharmaceutica Nv | Antiviral pharmaceutical compositions containing cyclodextrin and an antiviral agent |
| DE68924774T2 (en) * | 1988-07-07 | 1996-05-02 | Univ Pennsylvania | MODULATION OF VIRUS-HOST CELL INTERACTIONS USING CYCLIC OLIGOSACCHARIDES. |
| US5221669A (en) * | 1991-04-19 | 1993-06-22 | The United States Of America As Represented By The Department Of Health And Human Services | Antiviral compositions containing α-cyclodextrin sulfates alone and in combination with other known antiviral agents and glucocorticoids and methods of treating viral infections |
| US5296472A (en) * | 1991-12-05 | 1994-03-22 | Vyrex Corporation | Methods for delipidation of skin and cerumen removal |
| JP3101754B2 (en) * | 1994-01-25 | 2000-10-23 | 農林水産省食品総合研究所長 | Double-branched cyclodextrin with antibacterial activity |
| JPH11116410A (en) * | 1997-10-16 | 1999-04-27 | Takeda Chem Ind Ltd | Antifungal, mildew proofing and alga proofing composition |
| US6261540B1 (en) * | 1997-10-22 | 2001-07-17 | Warner-Lambert Company | Cyclodextrins and hydrogen peroxide in dental products |
| US6835717B2 (en) * | 2000-03-08 | 2004-12-28 | The Johns Hopkins University School Of Medicine | β-cyclodextrin compositions, and use to prevent transmission of sexually transmitted diseases |
-
2002
- 2002-02-01 DE DE10203999A patent/DE10203999A1/en not_active Withdrawn
-
2003
- 2003-01-20 WO PCT/EP2003/000505 patent/WO2003063882A1/en not_active Application Discontinuation
- 2003-01-20 AT AT03706365T patent/ATE431153T1/en not_active IP Right Cessation
- 2003-01-20 EP EP03706365A patent/EP1469866B1/en not_active Expired - Lifetime
- 2003-01-20 US US10/502,059 patent/US20050222080A1/en not_active Abandoned
- 2003-01-20 DE DE50311517T patent/DE50311517D1/en not_active Expired - Lifetime
- 2003-01-20 CN CNA038031671A patent/CN1627949A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| US20050222080A1 (en) | 2005-10-06 |
| DE10203999A1 (en) | 2003-08-14 |
| CN1627949A (en) | 2005-06-15 |
| ATE431153T1 (en) | 2009-05-15 |
| WO2003063882A1 (en) | 2003-08-07 |
| DE50311517D1 (en) | 2009-06-25 |
| EP1469866A1 (en) | 2004-10-27 |
| WO2003063882A8 (en) | 2004-12-29 |
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